Several tissues contain high-affinity binding sites for 3H-nitrendipine (3H-N) which may be associated with Ca channels. However, of these tissues, brain and skeletal muscle sarcoplasma reticulum (S.R.) are insensitive to this dihydropyridine (DHP) drug, whereas heart and smooth muscle are sensitive. Specific aims of this proposal are (1) a comparison of the biochemical properties of membrane 3H-N binding sites from pharmacologically sensitive and insensitive tissues; (2) the fractionation of cardiac muscle to determine the existence, density and characteristics of 3H-N binding sites in the sarcolemma, S.R. and a calsequestrin-containing subfraction of S.R.; (3) the chemical synthesis and biological activities of a limited series of DHP drugs designed to probe the differential fit of such agents into the 3H-N binding site; (4) the solubilization, purification and comparison of 3H-N binding sites from DHP sensitive and insensitive tissues; (5) preliminary determinations as to whether the membranous and also the purified 3H-N binding sites possess Ca channel properties. This proposal involves biochemical and pharmacological methodologies, plus organic synthetic work. It will advance our knowledge of the mechanism of action of DHP drugs, which have just been released in the USA as Ca channel blockers in coronary and cardiovascular disease, and of the relationship between 3H-N binding site and Ca channel in tissues possessing a binding site but insensitive to DHP drugs. It will also indicate whether skeletal and cardiac S.R. contain Ca channels and thus provide evidence for the mechanism of Ca release from these intracellular membranes.